Pentoxifylline, 1-(5-oxohexyl)-3,7-dimethylxanthine, is sold under the name Trental® in the U.S. and Canada. It is currently approved for the treatment of patients with intermittent claudication on the basis of chronic occlusive arterial disease of the limbs. It is also in clinical trials for glomerulonephritis, nephrotic syndrome, nonalcoholic steatohepatitis, Leishmaniasis, cirrhosis, liver failure, Duchenne's muscular dystrophy, HIV infection, late radiation induced injuries, radiation induced lymphedema, alcoholic hepatitis, radiation fibrosis, necrotizing enterocolitis in premature neonates, chronic kidney disease, pulmonary sarcoidosis, recurrent aphthous stomatitis, chronic breast pain in breast cancer patients, brain and central nervous system tumors, and malnutrition-inflammation-cachexia syndrome. Pentoxifylline has also recently garnered attention as a potential treatment for diabetes and disorders associated with diabetes. See Ferrari, E et al., Pharmatherapeutica, 1987, 5(1): 26-39; Raptis, S et al., Acta Diabetol Lat, 1987, 24(3):181-92; and Rahbar, R et al., Clin Chim Acta, 2000, 301(1-2): 65-77.
Pentoxifylline is known to have activity as an inhibitor of phosphodiesterase (PDE; see Meskini, N et al,. Biochem. Pharm. 1994, 47(5): 781-788) as well as activity against other biological targets, but its exact mode of action leading to clinical effects is unknown. Pentoxifylline has been shown to improve blood flow properties through hemorheologic effects which lower blood viscosity and improve erythrocyte flexibility. Pentoxifylline also increases leukocyte deformability and inhibits neutrophil adhesion and activation. (See FDA label for pentoxifylline at http://www.fda.gov/cder/foi/nda/99/74-962 Pentoxifylline_prntlbl.pdf). In addition to improving hemorheologic properties, pentoxifylline is also believed to have anti-inflammatory and anti-fibrotic properties.
The clinical pharmacology of pentoxifylline has been attributed to the parent drug as well as its metabolites, though the sequence of events leading to clinical improvement is still to be defined. Pentoxifylline undergoes rapid first pass metabolism. Peak plasma levels of pentoxifylline and its metabolites are reached within one hour. Structures of pentoxifylline and its various reported metabolites are shown below.
The major metabolites generated are M-1 and M-5. Plasma levels of these metabolites are five and eight times greater, respectively, than the parent drug. (See FDA label for pentoxifylline at http://www.fda.gov/cder/foi/nda/99/74-962_Pentoxifylline_prntlbl.pdf). The M-1 metabolite has a chiral center and both the (R)- and (S)-enantiomers are formed. During the metabolism of pentoxifylline, an interconversion takes place between the M-1 enantiomers and pentoxifylline. The (S)-enantiomer is the predominant M-1 species (ratio of S:R is reported to be approximately 90:10 or greater) and interconverts more rapidly than the (R)-enantiomer. The minor (R)-M1 metabolite (known as lisofylline) is reported to have novel anti-inflammatory properties.
While active M1 metabolite appears to play a central role in the clinical activity of pentoxifylline, other metabolites may contribute to drug toxicity. Notably, the risk of toxic reactions to pentoxifylline may be greater in patients suffering from renal impairment (http://products.sanofi-aventis.us/trental/trental.pdf). According to product labels, patients with renal impairment who take the drug require the monitoring of renal function. Moreover, at least one product label warns that pentoxifylline should not be administered to patients with severe renal or hepatic impairment. See Trental® Product Monograph, Canada, Dec. 16, 2008. In patients with renal impairment, it was reported that the plasma levels of pentoxifylline and M-1 exhibited a downward trend, while the levels of the M-4 and especially M-5 metabolite increased greatly depending on the degree of impairment. See Paap, Ann. Pharmacother., 1996, 30: 724. Taken together these observations suggest that accumulation of the M5 metabolite may be responsible for the reduced tolerability in patients with renal dysfunction.
Other compounds that are structurally related to pentoxifylline have been reported to be biologically active. Examples of such compounds include albifylline, torbafylline, A-802715, and propentofylline shown below.

Despite the beneficial activities of pentoxifylline, there is a continuing need for new compounds to treat the aforementioned diseases and conditions in a greater patient population while mitigating the risk of toxic reactions and other adverse effects.